Meyer SE, Qin T, Muench DE, Masuda K, Venkatasubramanian M, Orr E, Suarez L, Gore SD, Delwel R, Paietta E, Tallman MS, Fernandez H, Melnick A, Le Beau MM, Kogan S, Salomonis N, Figueroa ME, Grimes HL. DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia. Cancer Discov. 2016 May;6(5):501-15.
Mutations in the FLT3 and DNMT3A genes are frequently found in the same Acute myelogenous leukemia (AML). In Cancer Discovery, a research team demonstrated that combining mutations in the corresponding murine genes produces a spontaneous model of human AML. Notably, DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3-mutant myeloproliferative neoplasm into AML. Dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci, and varied in response to Dnmt3a levels.
Xu H, Chaudhri VK, Wu Z, Biliouris K, Dienger-Stambaugh K, Rochman Y, Singh H. Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8. Nat Immunol. 2015 Dec;16(12):1274-81.
Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts that secrete low affinity antibodies while others undergo affinity maturation in germinal centers (GCs) to generate plasma cells that produce high affinity antibodies. The Singh lab has identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulates the bifurcated humoral immune response. IRF8 dampens signaling via the B cell antigen receptor (BCR), facilitates antigen-specific interaction with helper T cells, and promotes affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. These regulatory factors are used as predictive biomarkers and also targeted to enhance vaccine responses.
Hall SL, Baker T, Lajoie S, Richgels PK, Yang Y, McAlees JW, van Lier A, Wills-Karp M, Sivaprasad U, Acciani TH, LeCras TD, Myers JB, Kovacic MB, Lewkowich IP. IL-17A enhances IL-13 activity by enhancing IL-13-induced signal transducer and activator of transcription 6 activation. J Allergy Clin Immunol. 2016 Jun 11. pii: S0091-6749(16)30430-4.
While pathogenesis of allergic asthma is widely regarded as mediated by Th2 cells and production of Th2-associated cytokines like IL-13, emerging evidence in both mouse and humans suggest that allergic asthma with a mixed Th2/Th17 inflammatory profile is typically more severe. As severe asthmatics are often refractory to commonly available therapeutics, and are at elevated risk of hospitalization or death as a result of their disease, we need a greater understanding of the unique processes governing more severe forms of disease. Work from the Lewkowich lab examining the role of IL-17A, a factor produced by Th17 cells associated with more severe disease begins to identify how Th2 and Th17-derived factors may interact to cause more severe disease. Compared to mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A displayed augmented airway hyperreactivity (AHR), mucus production, airway inflammation and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, co-exposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, IL-17A-driven elevation of IL-13-induced gene expression is associated with enhanced IL-13-driven STAT6 activation. These data represent the first mechanistic explanation of how IL-17A may directly contribute to the pathogenesis of IL-13-driven pathology.
Raynor J, Karns R, Almanan M, Li KP, Divanovic S, Chougnet CA, Hildeman DA. IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age. J Immunol. 2015 Aug 1;195(3):944-52.
Age-related immune suppression contributes to morbidity and mortality in aged individuals. In addition to intrinsic defects in lymphocytes, in collaboration with Dr. Chougnet, we have found that aged mice and humans have substantially increased levels of an immune-suppressive population of cells, so-called regulatory T cells (Treg). In this paper, we found that the Treg that accumulate with age are predominantly thymically derived. Interestingly, their accumulation relies on IL-6 signaling and the inducible co-stimulatory molecule, ICOS. Thus, these data illustrate a novel feedback mechanism, whereby pro-inflammatory signals (e.g. IL-6) provoke a negative feedback loop which engages an anti-inflammatory cell population that likely contributes to age-driven immune suppression.
Rueda CM, Moreno-Fernandez ME, Jackson CM, Kallapur SG, Jobe AH, Chougnet CA. Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function. Eur J Immunol. 2015 Sep;45(9):2582-92.
Regulatory T cells (Treg cells) are essential to maintain immune homeostasis. They exert their function in multiple targets, but their control of antigen-presenting cells is the most critical functionally. However, the functionality of neonatal Treg cells remains poorly characterized. We have developed an in vitro model in which Treg cell function are measured at a physiological ratio of Treg cells, conventional T cells and antigen-presenting cells. Using this model, we showed that neonatal Treg cells were only partially efficient, but this defect was not a reflection of the increased proportion of naïve Treg cells in infants. Prematurity did not appear to further affect Treg cell functionality. In addition, we identified CTLA-4 and cyclic AMP as the main suppressive molecules used by neonatal Treg cells. Altogether, our data imply a developmentally regulated maturation of Treg cell function. Furthermore, the decreased capacity of neonatal Treg cells to control antigen-presenting cell activation may contribute to the exacerbated inflammatory diseases seen in neonates, particularly in the context of in utero exposure to severe chorioamionitis.